Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, 221 (1982); D. J. Boullin, Serotonin in Mental Abnormalities 1:316 (1978); J. Barchas, et al., Serotonin and Behavior, (1973). Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
As a result of the broad distribution of serotonin within the body, there is a tremendous interest in drugs that affect serotonergic systems. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting. M. D. Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15:Supplement 7 (1990).
The major classes of serotonin receptors (5-HT1-7) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203. Recently discovered information regarding subtype identity, distribution, structure, and function suggests that it is possible to identify novel, subtype specific agents, having improved therapeutic profiles (e.g. fewer side effects).
For example, the 5-HT6 receptor was identified in 1993 (Monsma et al., Mol. Pharmacol. 1993, 43, 320-327; and Ruat, M. et al., Biochem. Biophys. Res. Com. 1993, 193, 269-276). Several antidepressants and atypical antipsychotics bind to the 5-HT6 receptor with high affinity and this binding may be a factor in their profile of activities (Roth et al., J. Pharm. Exp. Therapeut. 1994, 268, 1403-1410; Sleight et al., Exp. Opin. Ther. Patents 1998, 8, 1217-1224; Bourson et al., Brit. J. Pharm. 1998, 125, 1562-1566; Boess et al., Mol. Pharmacol. 1998, 54, 577-583; Sleight et al., Brit. J. Pharmacol. 1998, 124, 556-562). In addition, the 5-HT6 receptor has been linked to generalized stress and anxiety states (Yoshioka et al., Life Sciences 1998, 17/18, 1473-1477). Together these studies and observations suggest that compounds that antagonize the 5-HT6 receptor will be useful in treating disorders of the central nervous system.
Compounds of the present invention are radioligands of the 5-HT receptor (e.g., receptor-specific agonists or antagonists). Thus they are useful for identifying diseases wherein modulation of 5-HT activity is desired. Specifically, the compounds of this invention are useful in the diagnosis of psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, and sleep disorders. The compounds of this invention are also useful to identify psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia and the extrapyramidal motor side effects of other antipsychotic drugs. The compounds of this invention are also useful in the identification of eating behavior disorders.